Ylamines sympathomimetic process and compositions employing sulfonamidophenalk

ABSTRACT

Pharmaceutical compositions comprised of phenalkylamine compounds having both hydroxyl and sulfonamido groups in the phenyl ring are described. The sulfonamido-phenalkylamines are useful in decongestant and sympathomimetic processes.

United States Patent 11 1 Larsen et al.

[111 3,758,692 451 Sept. 11,1973

[73] Assignee: Mead Johnson & Company, Evansville, Ind.

22 Filed: Dec. 14,1970

21 Appl. No.: 98,129

Related [1.8. Application Data [60] Division of Ser. No. 817,272, April 14, 1969, Pat. No. 3,574,741, which is a continuation-in-part of Ser. No. 507,664, Nov. 15, 1965, abandoned.

[52] US. Cl 424/321, 424/244, 424/246, 424/248, 424/250, 424/267, 424/274 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/321, 267, 248, 424/244, 250, 246, 274

[56] References Cited UNITED STATES PATENTS 10/1959 Novello 424/321 3/ 1964 Larsen 12/1969 Loew 424/321 PrimarxExaminen-Sam Rosen WMW Att0rney-Albert H. Pendelton, Donald A. Peterson et al.

Annalee Pharmaceutical compositions comprised of phenalk- I ylamine compounds having both hydroxyl and sulfonamido groups in the phenyl ring are described. The sulfonamido-phenalkylamines are useful in decongestant and sympathomimetic processes.

8 Claims, No Drawings SYMPATHOMIMETIC PROCESS AND COMPOSITIONS EMPLOYING SULFONAMIDOPHENALKYLAMINES CROSS REFERENCE TO RELATED APPLICATIONS H It I AlkN R S O NH Formula I In this formula the OH and R S0,NH groups occupy any of the 2, 3, 4, 5, or 6-positions of the phenyl ring. The symbol Alk is analkylene group of two to five carbon atoms joining the phenyl ring and the aminonitrogen substituent 1 through two or three carbon atoms. It may be straight or branched. Examples of Alk groups are drawn below:

R is lower alkyl, alkenyl, cycloalkyl, or cycloalkenyl of up to six carbon atoms, phenyl, naphthyl, substituted phenyl, or substituted naphthyl. The substituents may be lower alkyl, alkenyl, cycloalkyl, cycloalkenyl, or

Examples of heterocyclic and heteropolycyclic groups are piperidine, morpholine, piperazine, indo-. line, 3-azabicyclo(2,2,2)-nonane, pyrrolidine, hexam'ethyleneimine, thiomorpholine, perhydroisoquinoline, tetrahydroisoquinoline, perhydlroquinoline, tetrahydroquinoline, l-(3-indoyl)isopropylamin'e, etc.

The group may also represent a simple primary secondary, or tertiary amino group. In such products R is hydrogen, alkyl, of no more than four. carbon atoms, or benzyl. R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, v cycloalkenylalkyl, polycycloalkyl, polycycloalkenyl, polycycloalkylalkyl, polycycloalkenylalkyl, aryl, aralkyl, aralkenyl, aryloxyalkyl, heterocyclic, heterocycloalkyl, heteropolycyclic, or heteropolycycloalkyl, each containing up to 10 carbon atoms and up to two substituents selected from hydroxyl, carboxyl, amino, halogen, methylenedioxy, RSO,NH, lower alkyl, or lower alkoxy of one to four carbon atoms.

The novel phenalkylamino compounds of the present invention are sympathomimetic amines of high potency. This discovery is surprising since it is known that neither hydroxyl substitution nor sulfamyl substitution in the phenyl ring of B-phenethylamine compounds results in a useful enhancement of activity. For instance, B-phenethylamine, B-phenylisopropylamine, and r the 4-hydroxy and 3,4-dihydroxy analogs thereof have only 1 to 2 percent the pressor activity of epinephrine, (G. A. A1les,,.l. Pharmacol. 47, 339 (1933)). 4'-('2- aminopropyl)methanesulfonanilide has been reported to be inactive (F. G. Holland, et al., J. Med. Chem. 6, 521 (1963)).

Those compounds of Formula I wherein R and R are hydrogen or lower alkyl groups of no more than two carbon atoms are pressor amines. For example, 5'- aminoethyl)-2'-hydroxymethanesulfon-anilide and 5'- (2-aminopropyl)-2'-hydroxymethanesulfonanilide are approximately equipotent as phenylephrine as pressor agents. One aspect of the present invention involves the discovery that 5'-[2-(cyclopropylamino)ethyl]-2- hydroxymethanesulfonanilide is a potent pressor amine similar in many respects to the aforesaid Z-aminoethyland 2-aminopropyl-2-hydroxymethanesulfonanilides.

' Compounds of Formula I wherein NRR moieties have lower alkoxy of up to 6 carbon atoms, or halogen, in-

eluding chlorine, bromine, iodine, or fluorine.

The amino group may be an N-substituted heterocyclic group having up to seven carbon atoms or an N-substituted heteropolycyclic group having up to l 1 carbon atoms in which the nitrogen atom is part of the heterocyclic ring when R and R are joined, either directly or through a nitrogen, sulfur, or oxygen atom. The Alk group is attached to the heterocyclic nitrogen atom.

about seven to 10 carbon atoms, such as a plurality of araliphatic groups, including phenethyl, phenoxyisopropyl, p-methoxyphenethyl, are generally depressor agents and frequently have a sympathomimetic action on smooth muscle.

The compounds of the present invention are characterized by remarkably low toxicities in relation to their activity, i.e., they have favorable therapeutic ratios.

The pressor substances offer the advantage of improved absorption on oral administration or through the mucous membranes on topical administration. The latter is of particular importance for nasal decongestant or vaso-constrictor use for treatment of certain conditions of the eye.

Dosage by the oral, parenteral, or rectal routes in the range 0.1 mcg. to 20 mg./kg. of body weight of host are to be employed. Many of the substances have acute LK values in excess of 2000 mg./kg. For topical use in the nose or eye, isotonic aqueous solutions having concentrations of about 0.1 to-10 percent by weight and containing preservatives and stabilizers as required are operable. Solutions of that concentration when sterile may be used for injection. Oil solutions or suspensions may also be employed. For oral use, tablets or capsules or liquid formulations such as solutions, suspensions in the form of syrups, or elixirs may be formulated containing from 5 to 50mg. of one of the present substances per dosage unit.

Pharmaceutical formulations of the present invention may be compounded with one of the novel sulfonanilides disclosed and claimed herein as the sole active ingredient or they may include other additional active ingredients, including tranquilizers, sedatives, analeptics,

analgesics, antipyretics, hypnotics, antibiotics such as polymixin, tyrothrycin, grammacidin, tyrocidin, and neomycin, antihistamines such as chlorprophenpyridamine maleate, or methdilazine hydrochloride, antiinflammatory agents such as cortisone phosphate, a surfactant, a chemical antiseptic such as thimerasol, benzalkonium chloride, or a mucolytic agent such as tyloxypal.

A preferred compound of the present invention due to its strong and selective adrenergic vasoconstrictor activity and its low toxicity is 5'-(2-aminoethyl)-2'- hydroxymethanesulfonanilide hydrochloride. For topical use for instillation into the nose or eyes, solutions formulated according to accepted pharmaceutical standards having concentrations of that compound of 0.05 to percent by weight are useful. For oral use dosage units containing 5 to 50 mg. thereof may be employed. FORMULATION 1.- Nose Drops.- A solution having a concentration of 0.5 percent of 5 2-aminoethyl)-2- hydroxymethanesulfonanilide hydrochloride is prepared by dissolving the following ingredients in sufficient distilled water to provide 1 l. of solution.

5 '-(2-aminoethyl)-2 -hydroxy-methanesulfonanilide hydrochloride 5.0 g.

sorbitol solution, N.F.

methylparabens 0.4 g.

propylparabens 0.2 g.

sodium citrate, U.S.P. 4.4 g.

sodium bisulfite, A.R. 1.0 g.

FORMULATION 2.- Tablets.- A scored tablet containing 10 mg. of 5-(2-aminoethyl)-2'-hydroxymethanesulfonanilide hydrochloride is prepared as follows: A dry blend of 57.0 g. of lactose, U.S.P. and 57.0 g. of mannitol powder is prepared and granulated with a 10 percent w/w starch paste containing 9.7 g. of corn starch, U.S.P. The moist granulation is screened through a No. 12 screen and dried at 130F. until the moisture is less than 2 percent. The dry granules are then reduced in size by shaking through a No. screen. The following materials are then blended with this screened granulation:

5 -(2-aminoethyl )-2'-hydroxy-methanesulfonanilide hydrochloride 10.0 g.

magnesium stearate 1.3 g.

The total weight of this preparation is 135 g. It is compressed into tablets each containing 10 mg. of 5'- (2-aminoethyl)-2-hydroxymethanesulfonanilide hydrochloride on conventional tableting equipment. FORMULATION 3- Ophthalmic Solution.- A buffered sterile ophthalmic solution containing 1.0 percent of 5 '-(2-aminoethyl)-2 '-hydroxyrnethanesulfonanilide hydrochloride is prepared from the following ingredients:

5 '-(2-aminoethyl )-2 '-hydroxy-methanesulfonanilide hydrochloride 5.0 g.

sodium biphosphate 3.2 g.

sodium phosphate, dibasic 0.95 g.

methyl cellulose, 4000 M.C. 3.0 g.

phenylmercuric acetate 0.02 g.

distilled water, 0.8. 1000 ml.

The resulting solution has a pH of 6.0 to 6.5. It is sterilized by filtration through a bacterial filter prior to filling into sterile ampules.

The phenalkylamine products of the present invention may be prepared by hydrogenolysis of the aliphatic hydroxyl group of the phenalkanolamine compounds of Formula II.

R 8 O N Formula II In Formula II, R, R and R have the same meaning to which the aliphatic nitrogen atom is attached corresponds in structure to Alk in Formula I. In other words,

is simply the Alk group of Formula I hydroxylated on the carbon atom attached to the benzene ring.

The intermediates of Formula II are described in U. S. Pat No. 3,341,584. The disclosure of this patent-is incorporated herein by reference to the extent that methods of preparation and working examples for the substances of Formula II are disclosed.

Reaction conditions for hydrogenolysis of the aliphatic hydroxyl of the substances of Formula II are known to those skilled in the art. Catalytic hydrogena-- tion conditions are generally preferred. We have'found that hydrogen pressures of from about 1m 6 atmospheres are adequate when 5 percent, palladium-om barium sulfate is the catalystand an acidic reaction medium is employed. The preferred acidic medium is glacial acetic acid containing a small amount of perchloric acid or other strong acid such as the mineral acids and Lewis acids including HCI, H 504. p+-CH C,H.S0,H, BF A1Cl,, etc. The hydrogenolysis method of preparing substances, of Formula I from'substances of Formula II is illustrated by Procedure 13. This method is applicable to thepreparation of all variations of the structure Formula I includingthose in which Alk contains either two or three carbon atoms separating .the benzene ring and the aminonitrogen atom. In those instances when R? of Formula II is benzyl, benzhydryl, or triphenylmethyl, it is removed in the course of the hydrogenation to provide the desired nuclear hydroxyl group of Formula I. The R t-butyl and t'etrahydro pyranyl groups when employed are subsequently removed by aqueous acid hydrolysis.

Another method for the preparation of compounds of Formula I from Formula II intermediates is the replacement of the B-hydroxyl group of Formula II with a halogen and subsequently dehalogenating the fl-halophenethylamine catalytically or with sodium borohydride. l

Those phenalkylamine products of Formula I in which Alk contains two carbon atoms in a chain separating NRR from the phenyl ring, that is compounds of the phenethylamine type,.may also be prepared from the RO, RSo Nll-substituted nitrostyrene derivatives of Formula III, which appears in the reaction scheme of Equations 1-4 below.

' mt'ixn ssqi Formula IV In Formula II R" and R haveas5.153155555358755 Formula II, and R refers to a hydrogen atom or a lower alkyl group of no more than 3 carbon atoms including methyl, ethyl, propyl, and isopropyl. Reduction of the nitrostyrene of Formula III by methods known inthe art such as catalytic hydrogenation or metal hydride reduction yields the corresponding phenethylamine compound in which R, R, and R have the same meaning as before. This transformation is shown in Equation 1.

The product of Equation 1 will be recognized as one of the substances of Formula I in which RO represents the phenolic hydroxyl group or equivalent as defined above for R, and in which R and R of Formula I are hydrogen atoms. These materials can be transformed into the corresponding intermediates of Formula IV in which R and R are substituent groups as defined for Formula I by alkylation of the side chain amino group with an alkylating agent having known capability of introducing substituents as defined for R and R into primary amines such as an alkyl halide, sulfate, or phosphate, or reductive amination with an aldehyde or ketone. This transformation is represented by Equation 2.

An alternative method for transformation of the nitrostyrenes of Formula III into the intermediates of Formula IV involves the reductive hydrolysis according to Equation 3 to the corresponding phenylacetaldehyde or benzyl alkyl ketone. One convenient method for accomplishing this involves reaction of the nitrostyrene with iron and hydrochloride acid. Other methods will be apparent by analogyto similar transformations known to the art.

The intermediate phenylacetaldehydes and benzyl .alkylketones produced by Equation 3 are convertible by reductive amina tion into the phenethylamine compounds of Formula IV employing ammonia or a primary orsecondary amine of the'formula RR NH. This transformation is represented by Equation 4. The process is carried out according to established techniques employing hydrogen and a catalyst as reducing medium or various chemical reducing agents such as zinc and acetic acid, sodium amalgum and ethanol, sodium and ethanol, or other reducingagents (Adams, Organic Reactions, Vol. 4, 1949, page l74255.) Preferred reaction conditions involve hydrogenation of a mixture of the carbonyl compound from Equation 3 and the desired amine or ammonia in a solvent such as acetic acid or ethanol over a platinum catalyst.

The nitrostyrene intermediates of Formula III are prepared by condensation of the correspondingly substituted benzaldehydes, Formula V, with a nitroparaffin the corresponding RO-nitrobenzaldehydes as is illustrated in Equations 5-8 by conversion thereof to the acetal, reduction of the nitro group to the amino group, and acylation of the amino group with the appropriate sulfonyl halideor anhydride. R has the same meaning in Formula V as previously.

v It is preferred that R be other than hydrogen for the processes of Equations 5-9, but this-is not essential. The acylation and hydrolysis procedures of Equations 7 and 8-may frequently be combined into a single step. For the preparation of the aldehydes of Formula V in which R is hydrogen, cleavage of R by hydrogenolytic methods should precede hydrolysis of the, acetal. Where hydrolytic methods are involved, these opera tions may be combined.

As a last step in the preparation of the products of Formula I according to the scheme outlined in Equations 1-4, it is sometimes necessary to include an additional reaction step to transform the R() substituent into the phenolic hydroxyl shown in Formula I. In other instances this transformation occurs concomitantly with the transformations indicated in Equations 1 or 2 or in Equations 3 or 4. In any event, adaption of the method to provide for this transformation is within the skill of the art. For example, where an affirmative step is necessary, hydrogenolysis over palladium catalyst or cleavage with soidum and liquid ammonia can be employed when R is benzyl, benzhydryl, or triphenylmethyl. Hydrolysis with dilute aqueous acid is used when R is t-butyl or tetrahydropyranyl. Those phenalkylamine products of Formula I in which Alk contains three carbon atoms in a chain separating NR R from the phenyl ring may also be prepared from the corresponding B-phenyl-propionic acids by conversion to the amide and reduction of amide to amine. These transformations are shown in Equations and 11.

EQUATIONS 10 AND 11 cmcmcont R 8 O NH The phenylpropionic acid starting material may, of course, bear additional alkyl substituents on the carbon atom alpha to the carboxylic function such as methyl or ethyl groups to provide a final product having a side chain corresponding to Alk in Formula I. The phenylpropionic acid starting materials are prepared from the aldehydes of Formula V by conventional means such as the malonic acid or malonic ester synthesis. Conversion of the acids to the amides in Equation 10 also employs known methods. Reduction thereof to the amines in Equation 1 l is most readily accomplished by metal hydride reduction.

PROCEDURE l.- 4-Hydroxy-3-nitrobenzaldehyde.- 4-Hydroxybenzaldehyde, 122.0 g. (1.0 mole), is added protionwise during a 30 min. period to 500ml. of red fuming nitric acid with stirring and cooling at -25 to 30C. Stirring is continued at -25C. for one hr., and the reaction mixture is then poured into 2 l. of crushed ice. The precipitate is collected, washed with water and air dried; yield, 162 g. (97 percent), m.p. 138144C. This material may be triturated with 500 ml. of ether and filtered to effect purification; yield, 153 g., m.p. l42145C.

PROCEDURE 2.- 4-Benzyloxy-3-nitrobenzaldehyde.- A mixture of 109 g. (0.54 mole) of -hydroxy-3- nitrobenzaldehyde, 83 g. (0.65 mole) of benzyl chloride, 72 ml. (0.72 mole) of ION potassium hydroxide,

5.0 g. (0.03 mole) of sodium iodide in 950 ml. of percent ethanol, and 250 ml. of water is stirred and refluxed for 48 hr. The reaction mixture is cooled and poured into 51. of ice water. The yellow solid which. precipitates is collected and washed with water. The

moist solid is triturated with dilute aqueous sodium hydroxide, filtered, washed repeatedly with water, and dried in a vacuum oven at45C.; yield, 79.5 g. (47.5 percent), m.p. 89-96C. Recrystallization from ethanol yields 63.0 g. of purified material, m.p. 96l00C., a small sample of which was recrystallized from ethanol for analysis, m.p. 97-l00C.

Anal. CAlcd. For C H No C, 65.36; H, 4.31; N, 5.45. Found: C, 65.09; H, 4.52; N, 5.69. PROCEDURE 3.- 4-Benzylo'xy-3-nitrobenzaldehyde Dimethyl Acetal.- Concentrated hydrochloric acid, 0.27 ml., is added dropwise to a stirred suspension of 128,5 g. (0.5 mole) of 4-benzyloxy-3-nitrobenzaldehyde in 190 ml. of absolute methanol. After stirring for one hr. at room temperature, 20g. of crystalline alumino silicate drying agent (molecular sieve Type 4A, Linde Company) is added and stirring is continued for 1.5 hr. The mixture is filtered and the filtrate made slightly alkaline with -metha'nolic sodium methylate. The solution is concen trated at reduced pressure, .the residual oil dissolved in 500 ml. of ether, and the ether solution washed with water and dried successively over anhydrous magnesium sulfate and anhydrous sodium. carbonate. The ether is evaporated at reduced pressure, leaving a viscous orange oil weighing 143.0 g. (94.5 percent). This material was reduced without further purification. PROCEDURE 4.- 3Amino-4-benzyloxybenzaldehyde Dimethyl Acetal. A solution of 4-benzyloxy-3-nitrobenzaldehyde' dimethyl acetal, 75.7 g. (0.25 mole) in 750 ml. :of ethanol is heated to reflux temperature with stirring. The heating bath is removed and five teaspoonfuls of moist Raney nickel catalyst is added. A solution of 99 percent hydrate, 37.5 g. (0.72 mole), in 35 ml. of ethanol is then added dropwise over a 30 min. period whilestirring. After an additional hour of reflux the mixture is filtered. The filtrate is concentrated-by distillation at reduced pressure, and the residue is extracted with 500 ml. of ether. The extract is driedover anhydrous magnesium sulfate and concentrated under reduced pressure yeidling an orange oil which crystallizes on standing; 64.8 g. (95 percent). Recrystallization of this material from isopropyl ether yields the purified product, m.p. 62-65C.

Anal. calcd. for C l-l NO z C, 70.30; H, 7.01;

N, 5.12. Found: C, 70.18; l-I,:7.10; N, 5.29.

PROCEDURE 5.- 2'-Benzyloxy-5'-formylmethanesul-- stirred at room temperature for 4.5 hr., the precipitated triethylamine hydrochloride removedby filtration, and the filtrate extracted with three 50 ml. portions of 1N aqueous potassium hydroxide solution..The aqueous extracts are acidified to precipitate the product. The

product is collected on a filter and washed with water;-

5.0 g., m.p. l58C. Recrystallization from isopro- 9 pyl alcohol yields the purified material weighing 2.5 g., m.p. 145-153c.

Anal. calcd. for C, H, -,NO,S: C, 59.00; H, 4.95; N, 4.59; S, 10.50. Found: C, 59,28; H, 5.25; N, 4.88; S, 10.61.

Methanesulfonic anhydride may be substituted as acylating agent in Procedure 5.

PROCEDURE 6.- 2'-Benzyloxy-5'-(2-nitrovinyl)methane-sulfonanilide.-

A mixture of 30.5 g. (0.1 mole) of 2-benzyloxy-5'- frmylmethanesulfonanilide, 2.0 g. of ammonium acetate, and 350 ml. of nitromethane is heated at 95-97C. for 5.5 hr. with stirring. The warm reaction mixture is filtered, and the filtrate diluted with isopropyl ether. The product precipitates and is collected on a filter and washed with isopropyl ether; 9.0 g., m.p. 165-170C. Concentration of the filtrate yields an additional portion weighing 7.8 g., m.p. 164-1 70C. RE- crystallization of the combined crops from ethyl acetate provides the purified product, m.p. 170-174C.

Anal. calcd, f r C,,H,,N,0,S: C, 55.16; H, 4.63; N, 8.04; S, 9.20. Found: C, 55.21; H, 4.69; N, 8.32;-S, 9.35.

PROCEDURE 7.- 2'-Benzyloxy-5'-(2-nitro-lpropenyl)-methanesulfonanilide.-

The method of Procedure 6 is applied to nitroethane as is ;describ ed in that procedure for nitro-methane. The product is obtained in the same fashion in 55 percent yield. It is recrystallized from ethyl acetate; m.p. l60-163C.

Anal. calcd. for C, H, N,O,,S: C, 56.34; H, 5.00; N, 7.73; S, 8.85. Found: C, 56.44; H, 5.23; N, 7.54; S, 8.95.

PROCEDURE 8.- 'r(2-Aminoethyl)-2'-benzyloxymethane-sulfonanilide Hydrochloride.- Y A solution of 7.2 g. (0.02 mole) of 2'-benzyloxy-5-(2- nitrovinyl)methanesulfonanilide in 75 ml. of dry tetrahydrofuran is added dropwise with stirring to a cooled suspension of 3.15 g (0.08 mole) of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran. After stirring for one hr. at room temperature, the mixture is filtered, the filter-cake extracted with three 250 ml. portions of boiling ethanol. The combined extracts are acidified with ethanolic hydrogen chloride and concentrated. The residue is triturated with a methanol-isopropyl ether mixture and collected; yield, 4.0 g. (54 percent), m.p. 201-215C. (dec.). This material is twice recrystallized from methanol-isopropyl ether to yield the purified product; m.p. 2l8-22lC.

Anal. calcd. for C,,H, N,O,S-HCl: (2, 53,84; 11, 5.93.

- Found: C, 54.12; H, 614.

10 Anal. calcd. for C H N O S-HCl: C, 40.52; H, 5.67; N, 10.50; S, 12.02. Found: C, 40.82; H, 5.78; N, 10.27; S, 12.00.

By application of Procedures 2, 3, 4, 5, 6, 8, and 9 used in preparing 5'-(2-aminoethyl)-2'-hydroxymethanesulfonanilide to other nitro hydroxy substituted benzaldehyde starting materials, a series of analogous products is produced having the hydroxyl and methanesulfonamido substituents oriented in various other positions of the benzene ring. This is illustrated in Table I.

PROCEDURE 10.- 2'-Benzyloxy-5 2- (isopropylamino)ethyl]-methanesulfonanilide Hydro- V chloride.-

A mixture of 3.5 g. (0.01 mole) of 5-(2-aminoethyl)- 2'-benzyloxymethanesulfonanilide (Procedure 8), 2.40 ml. (0.03 mole) of acetone, 0.63 ml. (0.01 mole) of acetic acid, and 0.25 g. of platinum oxide in ml. of absolute ethanol is hydrogenated at 40 psi until 0.01 mole of hydrogen has been absorbed. The reaction mixture is filtered. The filtrate is acidified with etha' nolic hydrogen chloride and evaporated to dryness at reduced pressure. The solid residue triturated with isopropyl alcohol-isopropyl ether, and then from ethanolether yields the pure product, m.p. 186-l93C.

Anal. calcd. For C,,,H ,N,O -,S'HCL: C, 57.20; H, 6.82; S, 8.04. Found: C, 57.28; H, 6.88; S, 8.13. PROCEDURE l1.- 5'-Acetonyl-2-benzyloxymethanesulfonanilide.-

To a stirred, refluxing mixture of 109.3 g. (0.302 mole) of 2 '-benzyloxy-5 2-nitro-l -propenyl )methanesulfonanilide (Procedure 7), g. of powdered iron and 3.0 g. of ferric chloride in 520 m1. of water there is added in dropwise fashion 52.0 ml. of concentrated hydrochloric acid. The reaction mixture is refluxed for two hr. following this treatment, and then filtered. The filter-cake is washed with water and twice triturated with 600 ml. of boiling methanol, yield, 55.3 g., m.p. l00104C. The filtrates are concentrated at reduced pressureto yield an additional .portion of product weighing 18.3 g., m.p. 94 -104C. The product is twice recrystallized from methanol, m.p. 102-106C.

Anal. calcd. for C, H,.NO,S: C, 61.24; H, 5.74; N, 4.20; S, 9.62. Found: C 6l.13; H, 5.99; N, 4.10; S, 9.76. PROCEDURE 12. 2'-Benzyloxy-5 2- (phenethylamino)propyl]-methanesulfonanilide Hydrochloride. I

A mixture of 6.1 g. (0.018 mole) of 5-acetonyl-2'- benzyloxymethanesulfonanilide, 4.4g. (0.036 mole) of B-phenethylamine 1.1 g. (0.018 mole) of glacial acetic acid, and 0.17 g. of platinum oxide in ml. of absolute ethanol is hydrogenated at 40 psi until 0.018 mole of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate acidified with ethanolic hydrogen chloride and concentrated at reduced pressure to give an oily solid. This material is triturated with isopropyl alcohol and filtered, yielding 5.3 g. of product, m.p. 140-l44C. An additional 0.3 g was obtained on evaporation of the filtrate. Recrystallization from 2- butanone yields purified material, m.p. 140144.5C.

Anal. calcd. for C H N O S-HCl: C, 63.20; H, 6.58; S, 6.75. Found: C, 63.24; H, 6.62; S, 6.84. PROCEDURE l3 2'Hydroxy-5 -[2- (isopropylamino)-ethyl]methanesulfonanilide Hydrochloride.- A mixture of 5.0 g. (0.0154 mole) of 2,-hydroxy-5'-( 1- hydroxy-2-isopropylaminoethyl)-methanesulfonanilide hydrochloride, 3.0 g., 5 percent palladium-on-barium sulfate, 3.0 ml. perchloride acid (70 percent), and 60 ml. glacial acetic acid is hydrogenated in a Parr shaker at 60 p.s.i. The reaction mixture is heated at 90C. during the process. When the calculated amount ofhydrogen has been absorbed, the mixture is cooled to room temperature and the catalyst and product are recovered by filtration. The filter-cake is triturated with 200 ml. hot ethyl alcohol, filtered while hot and concentrated under reduced pressure, resulting in recovery of 0.2 g. of starting material. The cake is then thoroughly triturated with hot ethyl alcohol (about 600 ml.), filtered while hot, and the filtrate concentrated under reduced pressure. Trituration of the residue with hot isopropyl alcohol yields 1.7 g. (31 percent) of the desired product, m.p. 258-259C., identical in all respects including mixed melting point with the product produced by Procedure 14. PROCEDURE l4.- 5-[ l-Chloro-2-(l-phenoxy-2-' propylam ino )-propyl] -2 -hydroxymethanesulfonanilide Hydrochloride.- Thionyl chloride (1.81 ml., 0.025 mole) is added in one portion to 2-hydroxy-5 l-hydroxy-2-( l-phenoxy-Z- propylamino )propyl]methane-sulfonanilide hydrochloride (4.3 g., 0.01 mole) suspended in 20 ml. acetonitrile and 4 drops of dimethylformamide. The mixture is refluxed until solution is effected (ca. min.). Isopropyl ether (50 ml.) is then added to the red-black solution forcing out an oil which is separated by decantation. Additional isopropyl ether (50 ml.) is added to the residual oil and the mixture stirred until tacky. The residue, which is separated by decantation, taken up in ml. of acetonitrile and warmed on a steam bath slowly deposits a tan solid 2.9 g. (64.5 percent), m.p. l60-162.5C. (dec.).

The analytically pure product is obtained by crystallizing this material from dimethylformamide acetonit- 12 rile; yield, 1.85 g. (41.3 percent), m.p. l64. 5165.5C-. (dec.) (corr.).

Calcd. for C,,,H ,Cl,N O,S: C, 50.78; H, 5.83; Cl, 15.78; N, 6.24. Found: C, 51.06; H,:5.84; C], 15.63; N, 6.36.

PROCEDURE l5.- 2-Hydroxy-5-[2-(4- methoxyphenethylamino)-propyl]rnethanesulfonanilide Hydrochloride.-

Treatment of 2 '-hydroxy-5 l-hydroxy-2-(4- methoxyphenethylamino)propyl]methanesulfonanilide hydrochloride (8.6 g., 0.02 mole) with thionyl chloride (2.6 g., 0.022 mole) according to the method of Procedure 14 provides 2'-hydroxy-5'-'[ l-chlo'ro-2-(4- methoxyphenethylamino)propyl]methanesulfonanilide hydrochloride.

The chloro compound is added portionwise in 15.

min. to a suspension of sodium borohydride (3.78 g., 0.1 mole) in absolute ethanol (100 ml.) at l0-l5C. After completing the addition, the mixture is stirred at room temperature for 0.5 hr., acidified with ethanolic hydrogen chloride and warmed to reflux for 5 min. and filtered. Dilution of the filtrate with 100 ml. of ether provides 6.1 g. percent overall yield) of white solid, m.p. l-l83.5C. (corr.).

Anal. calcd. for C,,,H CIN O S: C, 54.99; H, 6.56; N, 6.75; S, 7.73. Found: C, 55.25; H, 6.25; N, 6.75; S, 7.86.

PROCEDURE l6.- 2'-Hydroxy-5 '-[2-( l-phenoxy-Z- propyl-amino)propyl]methanesulfonanilide Hydrochloride.-

A suspension of 5'-[l-chloro-2-( l-phenoxy-2- propylamino)propyl]-2'-hydroxymethanesulfonanilide hydrochloride (7.45 g., 0.017 mole) in 250 ml. of absolute ethanol is reduced in an atmosphere of hydrogen employing 3.5 gof 10 percent palladium-on-carbon catalyst. Whn the. hydrogen up take ceases, the-mixture. is filtered. The filter-cake is extracted with 100 ml. of warm methanol. The methanol extract and ethanol filtrate are combined and the alcoholic solvents removed under .reduced pressure. The residue warmed with acetonitrile provides the phenethylamine product, m.p. 2032l2C. (5.8 g., percent). Crystallization of :this material from ethanolisopropyl ether affords analytically pure phenethylamine product, m.p. 22022lC. (corr.).

Anal. calcd, for C H ClN O,S: C, 54.99; H, 6.56; N, 6.75. Found: C, 54.89; H,6.50; N, 6.72.

Some representative substituted phenethylamines of the present invention prepared by the application of Procedures l-16 are given in Table; 11 along with precursors, procedure numbers, crystallization solvents, melting points and elemental analytical values.

TABLE III-SUBSTITUTED PHENETHYLAMINES Anplgsls (pea-t Example Proee- M.P. w No. Product Starting Material dure Recrystallization Solvent. 0.) Calcd. Found 1 5'-(2-:rmlnopropyl)-2-benzyl- 2-benzylox -5-2-nltr0-1- 8 2-propanol 137. 5440.5 0 55.05 54.75 oxymothanesulfonanllldo propenyl methanesulfonanl- H 6.25 6. 45 hydrochloride. lde hydrochloride. N 7.55 r 7.44 S 8. 46 8.71

2 5-(2-mnlnopropyl)-2-hydroxy- 5'-(2-amlnopropyl)-2'-benzy 9 Methanol-1S0 r0 lathe 21 -219 C motlmnesullonanlllde hydrooxymethanesulronsnlllde hyp py r (31ers) H Z?) S? chloride. drochlorlde. N 9. 98 9.77 S 11.42 11.38

3 2h-ydroxy-5-[2-(lsopropyl- 2-benzyloxy-5-[2-(lsopropy1 9 do 254;5258.6 C 46. 67 46. 66 amlno)ethyl]-methanesul amlno)ethyl]-metha.nesul- (dec.) H 6.85 6.71 fonunllide hydrochloride. tonanlllde hydrochloride. S 10. 38 10. 46 4 2-bcnzyloxy-5-(2-isopropyl- 5-(2-amlnopropy1)-2-benzy1 10' 2- r0 anol-lso r0 lethe 1 1 1 nmlnopropyD-methanesuloxymethanesulfonanillde p p p py rm 78- 83 1% 3:03 Tommi ldo hydrochloride. hydrochloride. S 7.76 7.90

Various substituted phenethylamine products having substituents corresponding to Table [I example numbers 2, 3, and 6 and the nuclear orientations of those listed in Table I may be prepared according to aforementioned procedures by application of the methods described to the nitrohydroxybenzaldehydes listed in Table I.

Various analogs of the foregoing compounds bearing opther sulfonamido groups RSO Nl-l, in place of the methane-sulfonamido group can be prepared by substitution of other sulfonylhalides or anhydrides for methanesulfonyl chloride in Procedure 5. To illustrate this specifically with reference to Procedures 5, 6, 8, and 9, there is listed in Table IV a series of suitable sulfonylhalides and anhydrides and the corresponding products obtainable therefrom.

TABLE IV VARIOUS 5 -(2-AMlNOETHYL)-2'-HYDROXY-RSO ANALIDES Product 5 2-Aminoethyl)-2'-hydroxyhexanesulfonanilide 5 2-Aminoethyl)-2'-hydroxybenzenesulfonanilide 5 2-Aminoethyl)-2'-hydroxy- (4-toluene )sulfonanilide 5 Z-Aminoethyl )-2 '-hydroxy- (2-chlorobenzene)sulfonanilide 5 2-Aminoethyl)-2'-hydroxy- (3-bromobenzene )sulfonanilide 5 2-Aminoethyl)-2'-hydroxy- (4-fluorobenzene)sulfonanilide Starting Material Hexanesulfonyl chloride Benzenesulfonyl chloride p-Toluenesulfonyl chloride o-Chlorobenzenesulfonyl chloride M-Bromobenzcnesulfonyl bromide p-Flurorobenzenesulfonyl chlorde p-Methoxybenzenesulfonyl chloride 5 -(2-Aminoethyl)-2'-hydroxy- (4-methoxybenzene)sulfonanilide 5 2-Aminoethyl)-2-hydroxy( lnaphthyl)sulfonanilide rx-Naphthalenesulfonyl chloride chloride 5 '-(2-Aminoethyl)-2'- hydroxy(2,5-dichlorobenzene)- sulfonanilide PROCEDURE l7.- 4-Benzyloxy-3-methanesulfonamido-benzaldehyde Dimethyl AcetaL- The preparation described in Procedure 5 is repeated as described, including the step of separating precipitated by-product triethylamine hydrochloride by filtration. The filtrate is then concentrated at reduced pressure until the solvent has been removed yielding an orange oil as residue. This material crystallizes on standing and is purified by trituration with isopropyl alcohol, m.p. 83-87C.

PROCEDURE l8.- 5-Formyl-2-hydroxymethanesulfon-anilide.- A mixture of 20 g. (0.057 mole) of 4-benzyloxy-3- methanesulfonamidobenzaldehyde dimethyl acetal (Procedure 17 2.5 g. of percent palladium-oncarbon, and 200 ml. of ethanol is hydrogenated at 60 p.s.i. until 0.057 mole of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to a residual oil weighing 12.5 g. The oil is dissolved in 25 ml. of warm ethanol, acidified with concentrated hydrochloric acid, diluted with 40 ml. of water, and chilled. The product crystallizes and is collected on a filter, washed with water, and

that the invention is notto be limited thereto, sincemany modifications may be made ,.and it is contemplated, therefore, by the appended claims, to cover any such modifications as fall within the spirit and scope of this invention.

What is claimed is:

l. The process of eliciting a sympathomimetic response in a mammalian host which comprises administering thereto 0.1 mcg..to 20 mg. per kilogram of body. weight of said host by the oral, parenteral or rectal routes, of a compound selected from the group consisting of HO R R SO NH and the pharmaceutically acceptable acid addition and metal salts thereof wherein Alk is an alkylene group of two to five carbon atoms joining the phenyl ring and the nitrogen atom through .two or three carbon atoms;

R is lower alkyl, phenyl, naphthyl, substituted phenyl, and substituted naphthyl wherein said substitu-. ent is halogen, lower alkyl, or lower alkoxy wherein each of said lower alkyl, and lower alkoxy groups have no more than six carbon atoms; and

is a heterocyclic group selected from the group consisting of piperidine, morpholine, piperazine, pyrrolidine, hexamethylene, and thiamorpholine, said group bonded to Alk through the nitrogen atom thereof or amino in which R is hydrogen, lower alkyl of no more than four carbon atoms, benzyl, or benzhydryl; and

R is l-(3-indolyl)-2-propyl, methylbicyclo-S- heptenyl, adamantyl, l-methyoxy-isopropyl, hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, 'cycloalkylalkyl, each containing no more than :l0 car- 1 no R1 Alk--N R3 n solNn 5 and the pharmaceutically acceptable acid addition and metal salts thereof wherein Alk is an alkylene grop of two to five carbon atoms joining the phenyl ring and the nitrogen atom through two or three carbon atoms;

R is lower alkyl, phenyl, naphthyl, substituted phenyl, and substituted naphthyl wherein said substituent is halogen, lower alkyl, or lower alkoxy wherein each of said lower alkyl, and lower alkoxy groups have no more than six carbon atoms; and,

is a heterocyclic group selected from the group consisting of piperidine, morpholine, piperazine, pyrrolidine, hexamethylene, and thiamorpholine, said group bonded to Alk through the nitrogen atom thereof or amino in which R is hydrogen, lower alkyl of no more than four carbon atoms, benzyl, or benzhydryl; and

R is l-(3-indolyl)-2-propyl, methylbicyclo-5- heptenyl, adamantyl, l-methoxy-isopropyl, hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, each containing more more than 10 carbon atoms, phenyl, phenyl-alkyl up to 10 carbon atoms, phenoxyalkyl up to 10 carbon atoms, substituted phenylalkyl and phenoxyalkyl wherein said substituent is selected from the group consisting of R sO Nl-l, lower alkyl of no more than four carbon atoms and lower alkoxy of more more than four carbon atoms.

4. The process of claim 3 wherein 5'-(2-aminoethyl)-,

2'-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed.

5. A liquid pharmaceutical composition suitable for parenteral or ophthalmic use, or application to the mucous membranes comprising a major proportion of a sterile liquid carrier and 0.1 to 10% by weight of a compound selected from the group consisting of HO R Alk-N and the pharmaceutically acceptable acid additionand metal salts thereof wherein is a heterocyclic group selected from the group consisting of piperidine, morpholine, piperazine, pyr- 18 rolidine, hexamethylene, and thiamorpholine, said group bonded to Alk through the nitrogen atom thereof or amino in which R is hydrogen, lower alkyl of no more than 4 carbon atoms, benzyl, or benzhydryl; and

R is l-(3-indolyl)-2-propyl, methylbicyclo-5- heptenyl, adamantyl,l-methoxydsopropyl, hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, each containing no more than 10 carbon atoms, phenyl, phenylalkyl up to 10 carbon atoms, phenoxyalkyl up to 10 carbon atoms, substituted phenylalkyl and phenoxyalkyl wherein said substituent is selected from the group consisting of RSO NH, lower alkyl of no more than four carbon atoms and lower alkoxy of no more than four carbon atoms.

6. The composition of claim 5 wherein 5 (2- aminoethyl)-2'-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed.

7. A pharmaceutical composition in dosage unit form adapted for oral administration comprising a major proportion of a pharmaceutical carrier and from 5 to 50 mg. of a compound selected from the group consisting of R SO NH and the parmaceutically acceptable acid addition and metal salts thereof wherein Alk is an alkylene group of two to five carbon atoms joining the phenyl ring and the nitrogen atom through two or three carbon atoms;

R is lower alkyl, phenyl, naphthyl, substituted phenyl, and substituted naphthyl wherein said substituent, is halogen,lower alkyl, or lower alkoxy wherein each of said lower alkyl, and lower alkoxy groups have no more than six carbon atoms; and,

Rll

isa lieter ocy clic group selected fro r n the group consisting of piperidine, morpholine, piperazine, pyrrolidine, hexamethylene, and thiamorpholine, said group bonded to Alk through the nitrogen atom thereof or amino in which R is hydrogen, lower alkyl of no more than 4 carbon atoms, benzyl, or benzhydryl; and R is l-(3-indolyl)-2-propyl methylbicyclo -5- heptenyl, adamantyl, l-methoxy-isopropyl, hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, each containing no more than 10 carbon atoms, phenyl, phenylalkyl up to 10 carbon atoms, phenoxyalkyl up to 10 carbon atoms, substituted phenylalkyl and phenoxyalkyl wherein said substituent is selected from the group consisting of RSO,NH, lower alkyl of no more than four carbon atoms and lower alkoxy of no more than four carbon atoms. 8. The composition of claim 7 wherein 5-(2- aminoethyl)-2'-hydroxymethanesulfonanilide or a is employed.

V UNITED, STATESPATENT} OFFICE CERTIFICATE 01 CORRECTION Patent: No. 3,758,692 Dated September 11, 1973 Inventofls) Aubrey A. Larsen and William A. p .q

It is certified that error appears in the above-identified patent and that said Letterslfatent are hereby corrected as shown below:

Col. 2, l. l4. After "primafy" ifisert a comma Col. 2, 1. 42 After"'5"-" insert (2- ll v ll, I V Col. 3, 1. e U LK shoeldbe I LD v c 1 5,, 1, -"(I)" overthe ar gow shouldbe (1) -1. v I I Col. 5 l. 36 "Formula II? shduldbe Formula III Col. 5, l. 65 'hYdIOChlQridG" should be hydrochloric Certificate of Correction U. S. Patent No. 3,758,692 Patented: September 11, 1973 Larsen, et a1.

Page Two Col. 7, l. 65 a Before "hydroxy3-" insert Col. 8, 1. 4 "51." should be 5 1.

Col. 8, 1. l3 CAlcd. For C H No should be Calcd. for C H NO Col. 8, l. 16 Line 17 should inunediately follow "Dimethyl" on'line 16 C01. 8, 1. l8 1 "128,5" should be 128.5

Col. 8, l. 34 Line'35 should immediately follow "Dimethyl" on line 34 Certificateof Correction U. S. Patent No. 3,758,692 Patented: September 11, 1973 Larsen, et a1.

Page Three Col. .40

Col. 11,

Before "hydrate" insert hydrazine 'yeildirig" should be yielding "C H NO should be C H NO "59,28" should be 59.28

"RE-" should be Re- Insert a-period after "g ."53,84" should be 53.84

"6l4' should be 6.14

Insert a comma after "C" Insert a period after "g Insert ahyphen (e) between "2' and "Hydroxy" Table II, bottom ll and 12, topof Cols.

l3 and 14 Certificate of Correction U. S. Patent No. 3,758,692 Patented: Larsen, et al. Page Four September 11, 1973- Col. 11, 1. l6 r Col. 12, 1. 36 v of Cols. I

"perchloride"should be -iperchloric "'Whn" should be When In thelastqcolumn heading insert a closing parenthesis after "weight" "Under column headed "Product",

for Example 3,

"Th-ydroxy" should be 7 2"-Jhydroxy Underthe column headed "Product" for Example 5,

"aminopropyo" should be aminopropyl Under the column headed "Starting Material" for Example 1,

"5'-2nitro---l-- should be "Under the column headed "Calcd.

for Example 1,

8.46"shouldbe s' 8.64

Certificate of Correction i U. S. Patent No. 3,758,692 Patented: September 11, 1973 Larsen, et al.- V Page Five Col. 13, 11. 39-40 ,Insert a hyphen after I 1"2" onflline u39 and delete the hyphen before. "methylaminoethyl" on l ne 40 TABLE III, Col. 14 EXAMPLEQSih PRODUCT column, i (aboutfl; 3 0) ins'er tfla V fhyphen between ,"2'" and 1 Y'Hydroxy."" I

EXAMPLE ZS in- PRODUCT column, "ethylshould be r 1 L a f EXAMPLE 3011 1 PRODUCT CQlumn,

insert a hyphen, after ','eth'y l] 'f. 4

v 32 in PRODUCT column, I insert a hyphen-() after "2" cal. 14, 4th line from v bottom a Show '33 '-f as last example number.

Certificate of- Correction U. S. Patent NO. 3,758,692

Patented: September 11, 1973 Larsen, et a1. 1 Page Six Col. 14 EXAMPLE 33 in'PRODUCT column and STARTING MATERIAL column,

insert aKhYphen after "propylamino) and "propylaminol respectively,

TABLE IV, Col. 15 IN PRODUCT'COLUMN':

l. 235 I insert a thyphen between ."hydroxy" and (1" 4 1. 38 insert a hyphen between 'hyd roxy"'}fan d (2," 41 "insert a fiiypheh between II ll (2 I II l. 44 insert e hyphenK between Col. 16, CLAIM'l, 1. 52

Col. 17,. CLAIM f3 ".hydroxy" and "(2,"

grop" should be ---f "R shouldbe R3 .Afterj "methylbicyclo" insert [2.2 .11

Certificate of Correction U. S. Patent No. 3,758,692 Patented; September 11, 1973 'Larsen, et a1.

Page Seven Col. 1?,

Col. 18,

Col. 18,

CLAIM 3,

CLAIM 5,

CLAIM 6,

CLAIM 7,

delete "more" (first occurrence) Signeci aridsealed this 6th day of August 1974.

(SEAL) Attest:

MCCOY M.GIBSON,"JR. Attesting Officer C; MARSHALL 'DANN Commissioner of Patents 

2. The process of claim 1 wherein 5''-(2-aminoethyl)-2''-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed.
 3. The decongestant process which comprises instilling into the nasal passages of a mammal an effective amount of a compound selected from the group consisting of
 4. The process of claim 3 wherein 5''-(2-aminoethyl)-2''-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed.
 5. A liquid pharmaceutical composition suitable for parenteral or ophthalmic use, or application to the mucous membranes comprising a major proportion of a sterile liquid carrier and 0.1 to 10% by weight of a compound selected from the group consisting of
 6. The composition of claim 5 wherein 5''-(2-aminoethyl)-2''-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed.
 7. A pharmaceutical composition in dosage unit form adapted for oral administration comprising a major proportion of a pharmaceutical carrier and from 5 to 50 mg. of a compound selected from the group consisting of
 8. The composition of claim 7 wherein 5''-(2-aminoethyl)-2''-hydroxymethanesulfonanilide or a pharmaceutically acceptable acid addition salt thereof is employed. 